Schizophrenia positive

The neurodevelopmental hypothesis of schizophrenia posits that the disorder is due to a subtle defect in prenatal brain development but is not clinically manifest until many years later (Murray and Lewis, 1987 Weinberger, 1987). This theory has two essential components a presumption of developmental neuropathology and an expectation that this developmental neuropathology results in a pattern of brain malfunction which ultimately produces the symptoms of schizophrenia. 

The dopamine hypothesis of schizophrenia posits that such symptoms arise because of a functional excess of dopaminergic activity in the CNS. The notion is based on the facts that drugs that activate DA receptors may cause psychotic symptoms and those that block DA receptors often have antipsychotic actions. However, drugs used for schizophrenia do not remedy all symptoms they are not curative, and some newer agents appear to be effective in many patients, even though they do NOT act as antagonists at brain DA receptors but may modify serotonin functions. 

The dopamine hypothesis of schizophrenia posits diminished dopaminergic activity in the prefrontal cortex and reciprocal dopaminergic hyperactivity in the mesolimbic pathways, associated presumably with the induction of negative and positive symptoms, respectively. The exact mechanisms responsible for such changes in dopaminergic transmissions are not yet fully understood. However, accumulated data suggest that altered (i.e. hypoactive) glutamatergic receptor expression/function may contribute to the observed abnormalities. 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Physical assessments include obtaining blood pressure measurements on both arms with the patient in a sitting position, pulse, respiratory rate, and weight. The hospitalized patient may ultimately be discharged from the psychiatric setting. Some patients, such as those with mild schizophrenia, do not require inpatient care. The nurse usually sees these patients at periodic intervals in the psychiatric outpatient setting. 

These are, of course, extracellular recordings but more recent intracellular studies in both rat and guinea pig accumbens slices show that DA produces a D2-mediated depolarisation and a Di hyperpolarisation which appear to be dependent on decreased and increased K+ conductances respectively. This would certainly fit in with the belief that DA mediates the positive effects of schizophrenia by a D2-mediated stimulation of the nucleus accumbens (see Chapter 17). 

Initiation of behaviour Mesolimbic pathway to nucleus accumbens from VTA (AIO) Mesocortical pathways to prefrontal cortex from VTA (AIO) Animals Increases locomotor activity and intracranial self-stimulation Humans Hallucinations, psychoses (reward, reinforcement) Animals Decreases activity and self-stimulation Humans Reduces positive symptoms of schizophrenia D2 ... 

On this evidence one can confidently equate EPS with neuroleptic DA receptor (D2) antagonism in the striatum and possibly a reduction in the positive symptoms of schizophrenia through similar action in the limbic system (nucleus accumbens). 

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug. 

Recognize the signs and symptoms of schizophrenia and be able to distinguish among positive, negative, and cognitive symptoms of the illness. 

For approximately 20% to 30% of people with schizophrenia, drug treatment is ineffective. A standard definition of treatment resistance includes patients who have persistent positive symptoms despite treatment with at least two different antipsychotics given at adequate doses (at least 600 chlorpro-mazine equivalents) for an adequate duration (4 to 6 weeks). In addition, patients must have a moderately severe illness as defined by rating instruments, and have a persistence of illness for at least 5 years.40 These patients are often highly symptomatic and require extensive periods of hospital care. 

Tandon R., Shipley J. E., Taylos S. et al. (1992). Electroencephalographic sleep abnormalities in schizophrenia. Relationship to positive/negative symptoms and prior neuroleptic treatment. Arch. Gen. Psychiatry 49,... 

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

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